A Case of Multiple Endocrine Neoplasia Type 2B
Masateru OhtaYukiko TokudaYuji SuzukiS KugeAkinori OkumuraMaki KubotaTetsuya TajimaR. Yoshiyuki OsamuraT Mitomi
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A sporadic case of multiple endocrine neoplasia type 2B in a twenty-six year old man who manifested medullary thyroid carcinoma, multiple mucosal neuromas of the tongue and a marfanoid habitus is reported. At the time of diagnosis, he also had multiple liver and lung metastases. Genetic analysis of his lymphocytes revealed a point mutation in exon 16 of the RET proto-oncogene. Since multiple endocrine neoplasia type 2B has a relatively poor prognosis because of the occasional aggressive behavior of medullary thyroid carcinoma, the necessity of the genetic diagnosis of multiple endocrine neoplasia in the early stage is suggested.Keywords:
RET proto-oncogene
Medullary carcinoma
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MEN1
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Introduction Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant hereditary disorder, associated with a cluster of germline gain-of-function mutations of the RET proto-oncogene ( RET ), mainly in exons 10–15. The G533C mutation in exon 8 of the RET is rare and has been mainly related to the familial medullary thyroid carcinoma. Patients-methods We describe the RET G533C mutation in exon 8 of the RET in two unrelated female index patients, with MEN2A phenotype, consisting of pheochromocytoma which was the presenting feature and medullary thyroid carcinoma. In addition, 12 family members were also studied. DNA extraction, PCR, and sequencing of RET was performed in exons 7–19 and 21, following standard procedures. Results The mutation was found in both index patients and in 6 out of 12 family members (50%). Three of them were biochemically affected with histologically proven medullary thyroid carcinoma in two of them while there are no certain clues regarding the other three members as they declined further evaluation. Conclusion Patients with MEN2A should be also searched in exon 8 while positive carriers of this mutation should be screened annually for pheochromocytoma or other components of the syndrome.
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Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.
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The RET proto-oncogene codes for a receptor tyrosine kinase thought to play a role in the development of neural crest and its derivatives. Mutations in the RET proto-oncogene have been found in patients with the multiple endocrine neoplasia type 2 syndromes (MEN 2), the related sporadic tumours medullary thyroid carcinoma and pheochromocytoma, and familial and sporadic Hirschsprung disease, a syndrome of congenital absence of enteric innervation. Germline mutations in one of eight codons within RET cause the three subtypes of MEN 2, namely, MEN 2A, MEN 2B, and familial medullary thyroid carcinoma. Somatic mutation in an overlapping group of nine codons have been found in a proportion of sporadic medullary thyroid carcinoma and pheochromocytoma. In contrast to MEN 2, approximately 25% of patients with Hirschsprung disease have germline mutations scattered throughout the length of RET. Hum Mutat 9:97–109, 1997. © 1997 Wiley-Liss, Inc.
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Multiple mutations in RET proto-oncogene are not common findings in patients with multiple endocrine neoplasia type 2A syndrome (MEN2A). Screening for RET mutation in MEN2A family members is usually limited by the known affected exon. However the second unrevealed mutation in RET proto-oncogene can coexist and modify the phenotype of MEN2 patients, including age of onset of medullary thyroid carcinoma, penetrance of pheochromocytoma etc. We here describe a family with MEN 2A syndrome with combination of three different germ-line RET mutations in its members (RET codon C634R, C634R+I852M, I852M+Y791F, Y791F). The earliest onset of medullary thyroid carcinoma was in a patient harboring the C634R+I852M double mutation at age 24 years. A 49-y.o.patient with C634R mutation has persistent medullary thyroid carcinoma after thyroidectomy at 35 years old. A carrier of Y791F mutation had no clinical evidence of disease at age of 28 years. In a child with compound I852M+Y791F mutation preventive thyroidectomy revealed C-cell hyperplasia at age of 4 years. The clinical significance of double RET mutation in the described family is not clear. Literature data of multiple germ-line RET mutations in patients with multiple endocrine neoplasia type 2A syndrome are presented.
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Frank-Raue K, Kratt T, Höppner W, Buhr H, Ziegler R, Raue F. Diagnosis and management of pheochromocytomas in patients with multiple endocrine neoplasia type 2—relevance of specific mutations in the RET proto-oncogene. Eur J Endocrinol 1996;135:222–5. ISSN 0804–4643 It has been suggested that specific mutations in the RET proto-oncogene correlate with clinical manifestation of the multiple endocrine neoplasia type 2 (MEN 2) syndrome. We retrospectively analyzed 61 patients with MEN 2, 28 with associated pheochromocytoma, regarding the relevance of specific mutations in the RET proto-oncogene and the diagnostic sensitivity of catecholamine screening and localization procedures. The present study shows that the position of the RET mutation is related to disease phenotype; codon 634 mutations are predictive of families predisposed to pheochromocytoma. In 18% of our patients, the diagnosis of pheochromocytoma preceded detection of medullary thyroid carcinoma. Therefore, mutation analysis of the RET gene should be performed in apparently "sporadic" cases of pheochromocytoma to confirm or exclude MEN 2. The most sensitive biochemical marker for pheochromocytoma in MEN 2 is 24-h urinary epinephrine excretion. Computed tomography, magnetic resonance imaging and MIBG scintigraphy are all highly sensitive methods to localize pheochromocytoma. We conclude that, in all families with MEN 2, mutational analysis of the RET proto-oncogene should be performed, both to identify gene carriers for MEN 2 and to identify specific mutations that are more strongly associated with pheochromocytoma. Karin Frank-Raue, Department of Internal Medicine, Endocrinology & Metabolism, Bergheimer Straße 58, 69115 Heidelberg, Germany
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The RET proto-oncogene codes for a receptor tyrosine kinase thought to play a role in the development of neural crest and its derivatives. Mutations in the RET proto-oncogene have been found in patients with the multiple endocrine neoplasia type 2 syndromes (MEN 2), the related sporadic tumours medullary thyroid carcinoma and pheochromocytoma, and familial and sporadic Hirschsprung disease, a syndrome of congenital absence of enteric innervation. Germline mutations in one of eight codons within RET cause the three subtypes of MEN 2, namely, MEN 2A, MEN 2B, and familial medullary thyroid carcinoma. Somatic mutation in an overlapping group of nine codons have been found in a proportion of sporadic medullary thyroid carcinoma and pheochromocytoma. In contrast to MEN 2, approximately 25% of patients with Hirschsprung disease have germline mutations scattered throughout the length of RET. Hum Mutat 9:97–109, 1997. © 1997 Wiley-Liss, Inc.
RET proto-oncogene
Proto-Oncogene Proteins c-ret
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Hirschsprung's disease
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